Respiratory viral infections in infants can have a significant impact on acute and chronic lung function. The most common respiratory infection in infants and the predominant cause of hospitalization in children (>90%) is respiratory syncytial virus (RSV). The impact that RSV and other respiratory viruses have on establishing the local pulmonary immune environment is not well understood and has a significant effect on long-term pulmonary disease, especially asthma. In the present revised proposal we will extend our focus from the previous funding cycles in which we investigated the role of cytokines and chemokines responsible for the activation and recruitment of leukocytes to the lung. Our published and preliminary data indicate that a key cell responsible for establishing a pathogenic immune environment is the dendritic cell (DC). While RSV, in particular, has been shown to alter DC activation and modulate important innate cytokines, especially type I IFN, little is known regarding the molecular and epigenetic regulation. Our hypothesis for this renewal application is that RSV infection modulates DC and promotes a more pathogenic environment by activation of a specific epigenetic enzyme, KDM5B H3K4 demethylase, that alters key innate cytokines, including type I IFN. Our findings build upon our previous studies and extend our knowledge by investigating a novel area of immunologic research to understand the molecular mechanisms governing the development of pulmonary disease. This proposal will address several important areas, including 1) what role do specific DC subsets have for promoting an altered immune response during RSV infection that enhances development of allergic disease, 2) identify what epigenetic enzymes are induced during RSV infection in DC that correspond to the altered immune environment, 3) examine the function of a specific epigenetic enzyme in vitro to determine its functional role in the process, and 4) determine the mechanism of KDM5B H3K4 demethylase in our in vivo model of RSV infection leading to enhanced allergen-induced disease. Studies using peripheral blood derived cells from adult and infants will enhance the clinical relevance of our findings in murine models and will characterized our findings for correlation with clinical disease.

Public Health Relevance

Respiratory virus infections can not only cause significant disease during primary infection of patients but also induction of secondary pulmonary disease sequelae in children and adults leading to long term complications. A better understanding of how viral-induced immune responses are epigenetically regulated, such as in RSV and other respiratory infections, will allow better diagnostic and therapeutic approaches for regulating the severity of subsequent diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
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Minnicozzi, Michael
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Ting, Hung-An; de Almeida Nagata, Denise; Rasky, Andrew J et al. (2018) Notch ligand Delta-like 4 induces epigenetic regulation of Treg cell differentiation and function in viral infection. Mucosal Immunol 11:1524-1536
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de Almeida Nagata, D E; Ting, H-A; Cavassani, K A et al. (2015) Epigenetic control of Foxp3 by SMYD3 H3K4 histone methyltransferase controls iTreg development and regulates pathogenic T-cell responses during pulmonary viral infection. Mucosal Immunol 8:1131-43
Ptaschinski, Catherine; Mukherjee, Sumanta; Moore, Martin L et al. (2015) RSV-Induced H3K4 Demethylase KDM5B Leads to Regulation of Dendritic Cell-Derived Innate Cytokines and Exacerbates Pathogenesis In Vivo. PLoS Pathog 11:e1004978

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